1. Field of the Invention
This invention is directed toward improved methods and compositions for inhibiting blood platelet aggregation.
2. Description of the Prior Art
A number of non-steroidal anti-inflammatory agents such as acetylsalicylic acid (aspirin), zomepirac, ibuprofen, naproxen, sulfinpyrazone, phenylbutazone and indomethacin have been found to be inhibitors of blood platelet aggregation. The presumed mechanism of action of such agents is inhibition of the blood platelet cyclooxygenase enzyme which ultimately leads to inhibition of collagen-induced platelet aggregation. Aspirin and sulfinpyrazone have been evaluated clinically for the prevention of stroke and heart attack and aspirin has been approved for prevention of transient cerebral ischemic attacks and stroke.
Anagrelide having the chemical name 6,7-dichloro-1,5-dihydroimidazo[2,1-b]quinazolin-2(3H)-one and the structural formula ##STR1## has been recently reported to be a potent inhibitor of platelet aggregation induced by a variety of aggregating agents. This potent activity has been observed in vitro in platelet rich plasma, ex vivo following oral dosing in animals and in several in vivo animal models following oral administration. Anagrelide has also been shown to inhibit aggregation when administered orally to man (Circulation 62: III-277, 1980). Anagrelide appears to be uniquely different from the non-steroidal anti-inflammatory agents in that it produces a broad spectrum effect, i.e. it blocks not only collagen-induced release and aggregation and the second wave of ADP (adenosine diphosphate)-induced aggregation but also the first phase of ADP-induced aggregation as well as aggregation induced by thrombin, arachidonic acid and antigen-antibody complex (Thrombosis Research 15: 373-388, 1979). Recent studies indicate that anagrelide acts in part by selective inhibition of blood platelet low K.sub.m cyclic AMP (adenosine monophosphate) phosphodiesterase (J. Lab. Clin. Med. 95(2): 241-257, 1980).
Certain blood platelet antiaggregation agents have been found to exhibit a supra-additive interaction when combined. Representative of such supra-additive combinations are the following:
1. Platelets and Thrombosis, A. Scriabine and S. Sherry (Eds.), Baltimore, University Park Press, 1974, pg. 247-262 at p. 256 discloses that a combination of acetylsalicylic acid and prostaglandin E.sub.1 exhibited supra-additive interaction against both collagen-and ADP-induced platelet aggregation. PA0 2. Fed. Proc. 38(3): 419 (1979) reports that supra-additive interaction is exhibited between combinations of anagrelide and prostaglandin I.sub.2 and combinations of anagrelide and prostaglandin I.sub.2 -S (the 6,9-thia analog of prostaglandin I.sub.2) with respect to ADP-or collagen-induced aggregation. PA0 3. Br. J. Exp. Path. 58: 474-477 (1977) discloses an in vivo supra-additive effect between acetylsalicylic acid and the antithrombotic agent SH 1117 with respect to ADP-induced aggregation. PA0 4. J. Lab. Clin. Med. 95(2): 241-257 (1980) discloses that anagrelide potentiates the inhibitory effect of prostaglandin E.sub.1 on platelet function and the prostaglandin E.sub.1 -induced elevation of cylic 3',5'-adenosine monophosphate (c AMP) basic level. PA0 5. U.S. Pat. No. 4,080,447 discloses the supra-additive interaction of acetysalicylic acid and ticlopidine with respect to blood platelet antiaggregation activity. PA0 6. U.S. Pat. No. 4,206,214 discloses that a combination of dipyridamole and sulfinpyrazone exhibits a supra-additive antithrombotic effect. PA0 7. French Pat. No. 2,390,959 (Farmdoc 14511B/08) discloses inter alia the supra-additive antiaggregation activity of acetylsalicylic acid and dipyridamole. PA0 8. Acta Univ. Carol. Med. Monogr. 72: 199-210 discloses in vitro supra-additive interaction with certain combinations of five drugs, i.e. metergoline, dipyridamole, acetylsalicylic acid, nimergoline and 5-adenosylmethionine.